Ziprasidone hydrochloride (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride), I is a potent neuroleptic agent useful in the treatment of psychotic disorders, schizophrenia, and anxiety diseases. It is currently marketed under the proprietary name of Geodon.

Ziprasidone hydrochloride is known to exist in various crystalline forms; namely, the monohydrate, hemihydrate and anhydrate form as disclosed in U.S. Pat. Nos. 4,831,031 and 5,312,925. As well, Canadian patent application 2,471,219 teaches an improved process for the preparation of ziprasidone hydrochloride anhydrate and other novel forms of ziprasidone hydrochloride monohydrate are described in WO 2004/089948 A1.
A considerable amount of effort has been devoted to improving the physical properties of ziprasidone hydrochloride, for instance in terms of the particle size, purity and water solubility of the finished product. Purported solutions include:
1) the use of ziprasidone hydrochloride having a mean particle size of less than 85 μm (U.S. Pat. No. 6,150,366);
2) the use of ziprasidone hydrochloride having a particle size greater than about 85 μm and less than about 300 μm (US 2005/049295 A1);
3) the use of water soluble clathrates of ziprasidone and its salts (WO 2004/054621 A1);
4) alternate salt forms such as the mesylate salt (Canadian patent 2,252,898);
5) pro-drugs of ziprasidone (U.S. Pat. No. 5,935,960); and
6) amorphous and other forms of ziprasidone hydrochloride (WO 2004/050655 A1 where the product has a water content of about 0.5% to 7.5%, most preferably 4.0 to 4.5%, Canadian patent application 2,467,538, and US 2005/0043324 A1).
Although the process taught in Canadian patent application 2,467,538 furnished highly pure ziprasidone hydrochloride, it required the use of a solvent in the salt forming step which had to be removed from the finished product in order to be used as a pharmaceutical ingredient. Noteworthy is that the preparation of active pharmaceutical ingredients (API's) must meet high purity specifications, for instance in terms of residual solvent content and to this end, regulatory authorities have set out quality guidelines regarding the permissible amounts of residual solvent in active pharmaceutical ingredients (for example, International Conference on Harmonisation, guideline Q3C). The use of a solvent also added to the cost of the finished product and increased the volumes required in the final step.
It is therefore very desirable to have a novel process for preparing amorphous ziprasidone hydrochloride in high yields and purity which is more reliable, consistent and suitable for large scale manufacturing, thus helping to overcome the deficiencies of the prior art, for instance the need to remove residual solvent from the ziprasidone hydrochloride. In addition, a new process to alternate acid addition salts of ziprasidone having improved qualities such as the bulk density and particle size would be desirable.